1) Field of the Invention
The present invention relates to the field of hydrogels and methods for their use.
2) Description of Related Art
A hydrogel is a network of polymer chains that are hydrophilic, sometimes found as a colloidal gel in which water is the dispersion medium. Hydrogels are highly absorbent (they can contain over 99.9% water) natural or synthetic polymers. Hydrogels also possess a degree of flexibility very similar to natural tissue due to their significant water content.
Hydrogels are used in a multitude of applications. Hydrogels are used in products as diverse as disposable diapers, contact lenses, EEG and ECG medical electrodes, and water gel explosives. Hydrogels are also used in many biotechnology-related applications. For example, hydrogels are used as scaffolds in tissue engineering and hydrogel-coated wells have been used for cell culture. Environmentally sensitive hydrogels have been created that have the ability to sense changes of pH, temperature, or the concentration of a metabolite and release their load as result of such changes. Hydrogels have also been created for sustained-release drug delivery systems. Some hydrogels are responsive to specific molecules, such as glucose or antigens, and can be used as biosensors.
Noninvasive externally-controlled hydrogel drug release systems are attractive since they allow remote, repeatable and reliable switching on or off of drug release based on need. Generally, a noninvasive remote-controlled drug delivery system comprises a drug, an external stimulus, stimulus-sensitive materials, and stimulus-responsive carriers. The external stimulus can be light, a magnetic field, or ultrasound or radio-frequency [Yavuz, M. S. et al., Nature Materials (2009) 8, 935; Sherlock, S. P. et al., Acs Nano (2011) 5, 1505; Lu, J. et al., Small (2008) 4, 421; Hoare, T. et al., Nano Letters (2009) 9, 3651; Thomas, C. R. et al., J. of the American Chemical Society (2010) 132, 10623; Li, W. Y. et al., Nanoscale (2011) 3, 1724; Santini, J. T. et al., Nature (1999) 397, 335; Grayson, A. C. R. et al., Nature Materials (2003) 2, 767].
An NIR light-triggered release system utilizes the photothermal property of a material, which absorbs NIR light and converts it into heat, thereby inducing the drug release from a thermosensitive carrier. Photothermal materials with strong optical absorbance in the NIR include various gold nanostructures (gold nanorods, gold nanocages, hollow gold nanospheres, gold nanoshells), carbon materials (carbon nanotubes, graphene), or conducting polymers that have been extensively studied for photothermal therapy [Markovic, Z. M. et al., Biomaterials (2011) 32, 1121; Yang, K. et al., Nano Letters (2010) 10, 3318; Tian, B. et al., Acs Nano (2011) 5, 7000; Yang, K. et al., Advanced Materials (2012) 24, 1868]. Gold nanoparticles, gold nanorods, and gold nanocages have been studied for the NIR-triggered drug release by incorporation into thermo-responsive materials [Yavuz, M. S. et al., Nature Materials (2009) 8, 935; Li, W. Y. et al., Nanoscale (2011) 3, 1724; Wu, G. H. et al., J. of the American Chemical Society (2008) 130, 8175]. However, none of these delivery systems have been advanced to clinical trials yet.
Two-dimensional graphene has received considerable attention in biomedical applications in the past few years owing to its high mechanical strength, pH sensitivity, photosensitivity and low toxicity [Yang, K. et al., Nano Letters (2010) 10, 3318; Yang, K. et al., Acs Nano (2011) 5, 516; Yang, X. Y. et al., J. of Materials Chemistry (2011) 21, 3448]. Graphene shows higher photothermal sensitivity than carbon nanotubes (CNT) and was shown to be highly effective in photothermal therapy for cancer [Markovic, Z. M. et al., Biomaterials (2011) 32, 1121; Yang, K. et al., Nano Letters (2010) 10, 3318; Tian, B. et al., Acs Nano (2011) 5, 7000; Yang, K. et al., Advanced Materials (2012) 24, 1868]. In addition, the highly efficient photothermal conversion of graphene enabled graphene oxide/pluronic hydrogel to undergo rapid gelation by NIR laser irradiation [Lo, C.-W. et al., Soft Matter (2011) 7, 5604; Sahu, A. et al., Chemical Communications (2012) 48, 5820]. Whether chemically reduced graphene oxide (GRAPHENE) is capable of acting as a photosensitive material for remote-controlled drug delivery has not been investigated yet.
As mentioned above, hydrogels have also been found to be advantageous when used as scaffolds for cell growth and, in particular, for tissue regeneration. Researchers have found that poor results are obtained when growing cells in a monolayer due to the vast differences in the monolayer cell environment and the in vivo cell environment. Cell morphology, extracellular matrix interactions, three-dimensional organization, oxygen tension, and access to extracellular factors all differ greatly between cells found in a monolayer and cells found in vivo.
Recently, three-dimensional cell cultures have emerged as an alternative to a flat layer of cells. Three-dimensional cell cultures are cellular networks organized in three dimensions—an environment that is much more similar to that found in vivo. Three-dimensional cell cultures have been created using tumor spheroids, embryoid bodies, hanging drop cell cultures, fibrous networks and hydrogels.
Hydrogels are an attractive scaffolding material because their mechanical properties can be tailored to mimic those of natural tissues. As scaffolds, hydrogels are used to provide bulk and mechanical constitution to a tissue construct, whether cells are adhered to or suspended within the three dimensional gel framework. When cellular adhesion directly to the gel is favored over suspension within the scaffold, incorporation of various peptide domains into the hydrogel structure can dramatically increase the tendency for cellular attachment. A particularly successful strategy to mediate cellular attachment is the inclusion of the RGD adhesion peptide sequence (arginine-glycine-aspartic acid). Cells that have been shown to favorably bind to RGD include fibroblasts, endothelial cells (ECs), smooth muscle cells (SMCs), osteoblasts, and chondrocytes. RGD in hydrogels, which can be incorporated on the surface or throughout the bulk of the gel, has shown enhanced cellular migration, proliferation, growth, and organization in tissue regeneration applications.